http://www.hepatitiscfree.com/interferon.html

AMERICAN LIVER FOUNDATION
Information 2002:
The Liver in Health and Disease

HEPATITIS C: THERAPY
Gary L. Davis, MD
University of Florida
Gainesville, Florida

Key Points:

  1. Chronic hepatitis C is a heterogeneous disease whose natural
history and  response to treatment is probably influenced by multiple
factors including but  not limited to viral genotype, level of viral
replication, and histology.

  2. Interferon is the only agent of proven efficacy in the treatment
of  hepatitis C. Standard treatment is interferon alfa-2b at a dose of
three million  units three times a week. The initial course of
treatment is 6 months, but  nearly all patients relapse and require
retreatment. The goal of interferon  treatment is suppression of
active disease; this usually requires long term  therapy. Eradication
of virus does not appear to be a realistic goal in most  patients

  3. Higher doses and longer duration of initial therapy have limited
benefit  over standard therapy. However, higher initial doses may
increase the interval  before relapse and escalation of the dose may
achieve response in some  non-responders.

  4. Treatment trials have tended to study relatively homogenous
patient groups  and the possibility of extrapolating these results to
different patient  populations is extremely limited. This is
especially true of studies from  geographic areas. Thus, future
studies should: (1) consider genotype, viral  load, and histology in
stratification; and (2) include a control group of  standard treatment
for comparison.

  5. Selection of patients for this chronic treatment remains
controversial.  Treatment of patients with active disease is most
cost- effective, but other  factors such as the degree of symptoms
must be considered.

  6. The definition of response to treatment is evolving as a
technology of  measurement of HCV improves. It is likely that future
treatment strategies will  be dependent upon virologic endpoints in
addition to, or instead of, serum ALT.

  7. Different agents and adjuncts have been incompletely studied to
date.  Ribavirin reduces serum ALT levels to normal and improves
fatigue in nearly half  of patients. Histology and virus levels do not
appear to be significantly  altered. The mechanism of its action of
this interesting agent is not clear.

INTRODUCTION

The first trial of interferon as therapy for chronic non-A, non-B
hepatitis  was reported in 1986. This pilot study demonstrated that
alpha interferon  therapy:
(1) was effective at low doses (in comparison to doses previously
shown  to be required for hepatitis B and D); (2) decreased serum ALT
levels promptly  upon initiation of therapy, a pattern suggestive of
an antiviral effect of  interferon; and (3) was usually associated
with relapse when treatment was  stopped, indicating a failure to
eradicate the virus. Many subsequent controlled  studies have now
confirmed all of these original observations. A dose of 3  million
units of recombinant interferon alfa-2b thrice weekly for 6 months is
the currently approved standard for initial therapy in the United
States. With  the discovery of the hepatitis C virus responsible for
non-A, non-B hepatitis  and the availability of moderately sensitive
techniques for detaching the virus,  it is now apparent that the
biochemical response to interferon (normalization of  ALT) is
associated with loss of detectable viremia; thus, the primary
response  it interferon is indeed due to the antiviral effects of the
drug. However, the  high relapse rate confirms the earlier suspicion
that interferon is usually  unable to eradicate the virus, which
persists at levels below the current limits  of detection in serum,
liver, or peripheral blood mononuclear cells.

It is apparent that the usual effect of interferon in patients with
chronic  hepatitis C who respond to this therapy is one of viral
suppression, not  eradication or cure. Sustained or prolonged response
to treatment (persistently  normal ALT levels) occurs in only 15-20%
of patients and is often associated  with detectable viremia despite
the biochemical absence of apparent hepatic  injury. The observations
from these early studies are important and must be  considered in
establishing appropriate justification and goals for interferon
therapy in clinical practice. Several crucial points must be made:

  1. Interferon therapy appears to eradicate or cure infection in
only a small  proportion of patients. Thus, cure is an unrealistic
goal of current interferon  regimens.
  2. Interferon is suppressive to the hepatitis C virus. The goal of
therapy  should be to suppress infection to a degree that liver
disease is minimized.
  3. The currently approved regimen of therapy (3 million units 3x
per week for 6  months) is suboptimal. It should be considered as
initial therapy, not as  definitive therapy. The goal of chronic viral
suppression will require prolonged  therapy, retreatment of relapse,
or maintenance regimens

Currently, clinical and basic research in hepatitis C is just
beginning to shed  light on the issues important to therapeutics in
this confusing disease. It is  now apparent that the disease course is
only slowly progressive in most  patients; thus, histology may be
important in assessing the timing of  therapeutic investigation. It is
evident that the natural history is different  between genotypes. The
initial and long-term response to therapy is also  effected by both
genotype and the level of viremia.

The differences in response to interferon therapy which occur as a
result of  viral differences are critical to clinical research in
therapeutics. Literally  dozens of studies of various interferon dose
regimens have appeared to  demonstrate superiority of every
conceivable permutation of dosing to the  currently accepted regimens.
However, few have compared these novel and  potentially useful
regimens to standard dosing. Since genotypes are  geographically
diverse and have significant influence on response to interferon,
trials conducted on one continent or even in different countries of
regions  within a continent are not comparable. Changes in therapeutic
regimens from the  current standard must be based on careful
comparisons of different regimens  among genotypically similar
patients with similar viral loads. It is likely that  a single dosing
strategy is not appropriate for all patients. Differences in the
hepatitis C virus from country to country may warrant local
modifications in  interferon dosing. Unfortunately, this implies that
the considerable effort and  expense of clinical trials may have
little applicability outside of the area  where they are conducted. At
a bare minimum, genotype and the degree of viremia  need to be
considered as stratification levels in designing future clinical
trials.

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These statements have NOT been evaluated by the FDA
and are for informational purposes only.

All images ©2001 Lloyd Wright
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